Sepsis is the leading cause of death in many intensive care units. It is the 12th leading cause of death in the United States and the incidence is increasing rapidly because of the growing number of immunosuppressed patients. Although the general consensus has been that sepsis represents a disorder due to uncontrolled inflammation, the failure of numerous anti- inflammatory strategies has led to a rethinking of this concept. Recent evidence in both animal models and in clinical studies of patients dying of sepsis and multiple organ failure indicates that sepsis causes extensive apoptotic cell death of lymphocytes throughout the body. This loss in lymphocytes may impair the ability of patients to eradicate infection and predispose to secondary infections. Interestingly, patients with inherited defects in lymphocytes have infections with many of the same organisms as patients in the intensive care unit. Furthermore, these patients also have difficulty eradicating infections. Recent studies in which lymphocyte apoptosis was prevented by two independent methods, i.e., overexpression of the anti-apoptotic protein Bcl-2 or administration of drugs that prevent cell death proteases (caspase inhibitors), have shown a marked improvement in sepsis survival. The focus of this investigation is to determine, using transgenic mice models and adoptive transfer of lymphocytes, which lymphocyte subsets, i.e., CD4 helper T cells, CD8 cytotoxic T cells, or B cells, are critical for sepsis survival. The changes in lymphocyte effector function that occur in survivors vs. non-survivors will also be determined. Two other potential mechanisms of immune suppression in sepsis will be examined including: 1) effects of apoptotic cells to induce anti-inflammatory responses and, 2) a shift in the pattern of cytokine expression from the pro-inflammatory Th1 to the anti- inflammatory Th2.